The journal of allergy and clinical immunology. Global · 2025
B-cell immunodeficiency associated with polynucleotide kinase 3'-phosphatase (PNKP) deficiency.
СтатьяНазвание и аннотация: Перевод в очереди
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Takada Sanami, Okano Tsubasa, Tanita Kay, Tsukada Kaima, Watanabe Masato, Hijikata Atsushi, Naruto Takuya, Yeh Tzu-Wen, Kasuga Saki, Tokimasa Sadao, Taniguchi-Ikeda Mariko, Ogata Reina, Ikeda Azusa, Goto Tomohide, Osaka Hitoshi, Takagi Masatoshi, Imai Kohsuke, Morio Tomohiro, van der Burg Mirjam, Shimada Mikio, Kanegane Hirokazu
Аннотация
BACKGROUND: DNA repair is crucial for maintaining genomic integrity and plays a significant role in the immune system. Defects in DNA repair pathways are often associated with immunodeficiency, including B-cell defects, which are consistent with the need for DNA repair during V(D)J recombination, class switching, and somatic hypermutation during B-cell maturation. Polynucleotide kinase 3'-phosphatase (PNKP) plays a significant role in DNA repair. PNKP deficiency is characterized by neurologic developmental abnormalities; however, immunodeficiency has not yet been reported.
OBJECTIVE: We focused on a pair of PNKP-deficient siblings who presented with microcephaly, eye abnormalities, and hypogammaglobulinemia. We aimed to analyze the effect of PNKP deficiency on B-cell development.
METHODS: Whole-exome sequencing was performed to identify the genetic cause of hypogammaglobulinemia. DNA repair efficiency was analyzed using patient-derived fibroblasts. The immune phenotype and B-cell receptor repertoire were analyzed using the patient's peripheral blood, alongside other patients with PNKP deficiency without severe immunodeficiency.
RESULTS: Whole-exome sequencing revealed compound heterozygous PNKP variants. Fibroblasts revealed defects in DNA repair in response to radiation-induced double/single-stranded DNA breaks. Flow cytometry revealed reduced total B-cell and class-switched memory B-cell counts. The B-cell receptor repertoire analysis demonstrated reduced frequencies of somatic hypermutations in these patients, whereas other patients with PNKP deficiency exhibited normal B-cell receptor repertoire patterns.
CONCLUSION: Our case indicated that PNKP variant-induced DNA repair abnormalities may be associated with immunodeficiency.
OBJECTIVE: We focused on a pair of PNKP-deficient siblings who presented with microcephaly, eye abnormalities, and hypogammaglobulinemia. We aimed to analyze the effect of PNKP deficiency on B-cell development.
METHODS: Whole-exome sequencing was performed to identify the genetic cause of hypogammaglobulinemia. DNA repair efficiency was analyzed using patient-derived fibroblasts. The immune phenotype and B-cell receptor repertoire were analyzed using the patient's peripheral blood, alongside other patients with PNKP deficiency without severe immunodeficiency.
RESULTS: Whole-exome sequencing revealed compound heterozygous PNKP variants. Fibroblasts revealed defects in DNA repair in response to radiation-induced double/single-stranded DNA breaks. Flow cytometry revealed reduced total B-cell and class-switched memory B-cell counts. The B-cell receptor repertoire analysis demonstrated reduced frequencies of somatic hypermutations in these patients, whereas other patients with PNKP deficiency exhibited normal B-cell receptor repertoire patterns.
CONCLUSION: Our case indicated that PNKP variant-induced DNA repair abnormalities may be associated with immunodeficiency.